DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim to priority from Provisional Applications Nos. 63/292,581 filed 12/22/2021 and 63/340,254 filed 05/10/2022, is hereby acknowledged.
Application Status
Amendments filed 02/13/2026 are hereby acknowledged. Claims 1-95 are cancelled. Claim 96 is currently amended. Claims 96-99 are pending and under examination in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and/or arguments and is withdrawn.
The following rejections are maintained from Office Action dated 11/14/2025, but modified as necessitated from Applicant’s amendments:
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 96-99 are rejected under 35 U.S.C. §103 as being unpatentable over Brown (Brown, B.D. et al. WO2021/188795 A1; International publication date September 23, 2021; priority based on provisional 62/991,335, March 18, 2020; previously cited) in view of Pisciotta (Pisciotta, L. et al. “Characterization of three kindreds with Familial Combined Hypolipidemia caused by loss-of-function mutations of ANGPTL3”. Circulation, Cardiovascular Genetics, Vol. 5 , No. 1 (2012), pp: 42-50), Zou ( Zou, H. et al. “Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C study”. Cardiovascular Diabetology, Vol. 20 (2021), p: 127), Aleksandrov (Aleksandrov, V. et al. “The Role of Angiopoietin-like proteins types 3 and 4 in the development of renal dysfunction in patients with rheumatoid arthritis”. Annals of the Rheumatic Diseases. Vol. 80. Suppl.1 (June 2021) Scientific Abstracts-AB0053, p:1059), Wang (Wang, Q. et al. “Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis”. European Heart Journal, Vol. 42 (published online Dec. 22, 2020, print version published March 2021), pp: 1160-1169), and Li (Li, Y. et al. Acta Biochemi. Biophys. Sin. Vol.40 (2008), pp: 459-465; previously cited).
Regarding claim 96, Brown teaches a method of treating a
subject having a kidney disease (chronic kidney disease, see § [00193]), the method comprising administering an Angiopoietin Like 3 (ANGPTL3) inhibitor to the subject (see claims 48, 52, 53, 54, 55).
Brown is silent about, and does not teach, a nephrotic syndrome nor a renal cell carcinoma. But since Brown teaches a chronic kidney disease (see § [00193]), it is interpreted as “not a nephrotic syndrome” and “ not a renal cell carcinoma”.
Brown teaches a human as the subject having a disease, disorder or condition associated with ANGPTL3 expression, that would benefit from reducing ANGPTL3 expression (see § [0076], [00175], and [00199]).
Brown teaches the use of an ANGPTL3 inhibitor in a subject that could benefit from decreasing the level of ANGPTL3 in a subject having a disease or condition associated with the expression of ANGPTL3 (see § [0084], [0175] and [00193]).
Brown teaches an inhibitory oligonucleotide capable of hybridization with ANGPLT3’s nucleotide sequence and reducing ANGPTL3 expression (see § [0072], [0091], and claims 1-6, 20). Brown teaches that the inhibitory oligonucleotide can be a small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), dicer substrate interfering RNA (dsiRNA), antisense oligonucleotide, short siRNA, single-stranded siRNA, or a double-stranded RNAi oligonucleotide (see [0068], [0097]-[00100]).
Brown teaches that the method of treating can include selecting a subject having a disease, disorder or condition associated with ANGPTL3 expression or is predisposed to the same (See § [00176]). Brown also teaches that the method can include selecting an individual having a marker for ANGPTL3 expression such as elevated TG (triglycerides) or cholesterol or is predisposed to the same (See § [00176]).
Brown is silent on a specific genotype. It is interpreted that the treatment could benefit anyone with a condition resulting from dysregulation of ANGPTL3 gene expression, independently of specific mutation inside ANGPTL3 gene.
Brown does not teach a subject heterozygous for an ANGPTL3 predicted loss-of-function or missense variant nucleic acid molecule.
Brown does not teach a relationship between a subject heterozygote for a loss-of-function or missense variant in ANGPTL3 gene and improved kidney function.
However, Pisciotta teaches one of the missense mutation listed in instant claim 78, which recites “wherein the predicted loss-of-function or missense variant nucleic acid molecule is variant (…)1: 62604236” (third variant from the end, at end of list) (see Pisciotta, “Abstract” section and page 44, figure 1).
The NCBI search connects the mutation located at 1: 62604236 to rs 398122985 which is c.1198+1G>T (p.G400VfsX5) mutation. The NCBI page as shown below, provides links to PubMed citations, one of which refers to Pisciotta.
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Pisciotta teaches that loss-of-function mutations in ANGPTL3 contribute to familial combined hypolipidemia (see title). Pisciotta confirms the correlation of rs 398122985 with the polymorphism c.1198+1G>T (p.G400VfsX5) in ANGPTL3 loss-of-function mutations in subjects with familial hypobetalipoproteinemia 2 (see page 44, figure 1).
A verification of the position in updated annotated nucleic acid sequence shows the SNP positioned on chromosome 1 at Chr1: 62604236 (see above):
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Pisciotta teaches the analysis of sequence of ANGPTL3 gene through sequencing to identify subjects with loss-of-function mutations (see page 43, right column, “Sequence of ANGPTL3 gene” section).
Claim 96 also recites “wherein the ANGPTL3 heterozygosity improves kidney function”.
MPEP 2112.01 states “when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent”.
Therefore, this limitation in claim 96 is drawn to a characteristic, a consequence, of being an ANGPTL3 LOF mutation heterozygote carrier, and not a claimed method step.
Brown and Pisciotta do not teach the claimed inherent properties of subjects carrying a LOF ANGPTL3 mutation.
However, Zou, Aleksandrov, Wang and Li provide teachings consistent with the inherent properties of a loss-of-function mutation in ANGPTL3 gene.
Zou teaches that structurally related ANGPTL8 protein (see page 6, left column, second paragraph), although important regulator of lipid metabolism, is associated with the risk of kidney function decline in a cohort study (see abstract). Zou teaches an association between circulating levels of ANGPTL8 and chronic kidney disease (CKD) (see page 2, third paragraph). Zou teaches that ANGPTL8 not only has considerable structural similarity with ANGPTL3, but is also known to form a complex with ANGPTL3 to inhibit lipoprotein lipase (see “Background” section, pages 1-2).
Zou also teaches subjects with higher stages of CKD (> or = 3) and End-stage renal disease (see abstract section; see page 2, right column, “Outcome assessment” section). Zou also teaches the estimation of glomerular filtration rate (eGFR) as a measure of kidney function (see Table 1; see page 2, right column, “Outcome assessment” section).
Aleksandrov teaches a direct role of ANGPTL3 in subjects with inflammation (rheumatoid arthritis) in the development of renal dysfunction (see title). Aleksandrov teaches a negative correlation between the level of ANGPTL3 and glomerular filtration rate (see left column, “results” section).
Aleksandrov also teaches estimation of kidney function using GFR (glomerular filtration rate) and CKD stages C4-5 (see “Methods” section).
Wang teaches genotypes associated with lower concentrations of inflammatory biomarkers, improved insulin-glucose metabolism, lower risk of coronary heart disease, type 2 diabetes and improved kidney function (see pages 1160-1161, “Methods and results section of summary). Wang teaches that genetic mimicry of ANGPTL3 inhibition is associated with improved kidney function (see page 1161, “Methods and results section of summary). Wang further suggests to assess the role of ANGPTL3 inhibitors in possible prevention and treatment of kidney diseases in trials (see page 1167, left column, first paragraph).
Li teaches that ANGPTL3 modulates the properties of human glomerular endothelial cells (see title). Li also teaches that ANGPTL3, secreted by podocytes, alters the human glomerular endothelial cell barrier properties and is involved in the pathophysiology of the development of proteinuria, a sign of kidney damage/disease (see page 460; left column, lines 28-38).
Li teaches that adding ANGPTL3 to a monolayer of glomerular endothelial cells alters the trans-endothelial electrical resistance (TEER), and increases the passage of BSA (Bovine Serum Albumin) through the monolayer (see Figures 1 and 2), i.e. proteinuria. Therefore, Li teaches that ANGPTL3 increases the permeability of the glomerular endothelial cell layer and contribute to glomerular endothelium filtration dysfunction.
Li teaches that an inhibitor of the signal pathway such as LY294002 (PI3K inhibitor) could block the ANGPTL3-induced phosphorylation of Protein Kinase B and its involvement in decreasing TEER (see Figure 4). Therefore, Li teaches that using an inhibitor interfering with ANGPTL3 signal pathway, reverses the negative effect of ANGPTL3 on TEER and barrier permeability.
Therefore, it would have been obvious to one with ordinary skills before the effective filing date of the claimed invention to have combined the method of treating chronic kidney disease taught by Brown using Brown’s ANGPTL3 nucleic acid inhibitor with the genetic analysis identifying loss-of-function mutations in ANGPTL3 gene in subjects, as taught by Pisciotta. Combining the teachings of Brown with Pisciotta would lead to a method of treating chronic kidney disease with a selection method for subjects likely to benefit from treatment, i.e., subjects having a heterozygous LOF mutation in ANGPTL3. The modified method of treating is rendered obvious in view of Zou, Aleksandrov, Wang and Li’s teachings.
It is interpreted that subjects having a heterozygous loss-of-function mutation such as the one described by Pisciotta, will likely have a better kidney function compared to wild-type ANGPTL3 carriers, while homozygous carriers of the same mutation will not be in need of treatment, since they will likely present with lowest to null levels of expressed/serum ANGPTL3 protein.
One with ordinary skills in the art would have considered the teachings of Zou, Aleksandrov, Wang and Li, since Wang teaches that genetic mimicry improves kidney function and Li shows a direct involvement of ANGPTL3 in the barrier function of renal glomerular endothelial cells. One with ordinary skills in the art before the effective filing date of the claimed invention, would have combined the teachings of Brown, Pisciotta, Zou, Aleksandrov, Wang and Li and would reasonably conclude that a deficiency in ANGPTL3 would be favorable to glomerular endothelium and kidney function. It would have been obvious to verify and assess the kidney function as taught by Zou and Aleksandrov using eGFR and correlate with ANGPTL3 serum levels and disease stage and progression. One with ordinary skills in the art would also be motivated in selecting subjects with wild-type genotype, or heterozygote for the LOF mutation in ANGPTL3 since these subjects would likely respond to treatment, would have performed the modification in Brown’s Method of treating and arrived at the claimed invention with a reasonable expectation of success.
Regarding claims 97-99, Brown teaches that the method of treating includes reducing the frequency or severity of at least one sign, symptom or contributing factor of a condition (see [0080]).
Brown modified by Pisciotta does not teach a method for treating severe chronic kidney disease or different stage of kidney disease.
However, Zou teaches subjects with higher stages of CKD (> or = 3) and End-stage renal disease (see abstract section; see page 2, right column, “Outcome assessment” section). Zou also teaches the estimation of glomerular filtration rate (eGFR) as a measure of kidney function (see Table 1; see page 2, right column, “Outcome assessment” section).
Aleksandrov also teaches estimation of kidney function using GFR (glomerular filtration rate) and CKD stages C4-5 (see “Methods” section).
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Brown modified by Pisciotta, in view of Zou and Aleksandrov, and included subjects at different severity and stage of kidney disease to treat. One with ordinary skills in the art, motivated in trying and stabilizing and/or reversing the symptoms of severe kidney disease, would have performed this modification to the treatment protocol, and used the eGFR as a measurable end-point, with a reasonable expectation of success and arrived at the claimed invention.
The obviousness of the combination of references Brown, Pisciotta, Zou, Aleksandrov, Wang and Li is also described above.
Response to Arguments
Applicant's arguments filed 02/13/2026 have been fully considered but they are
not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding Applicant’s arguments, see Remarks filed 02/13/2026, pages 4-5, in
response to applicant’s argument that Zou is not directed to ANGPTL3, but to ANGPTL8, which is a different protein, Zou teaches that a structurally related protein that forms a complex with ANGPTL3, i.e. ANGPTL8, is related to kidney dysfunction (see title). Therefore, since as part of ANGPTL3 signaling pathway, ANGPTL8 plays a relevant role, documentation regarding impact of ANGPTL8 is relevant, especially in a case where there is a need for treating an ANGPTL3-related dysfunction, not presenting with a clear genotype with a loss-of-function mutation in ANGPTL3 gene. Thus, a possible mutation leading to ANGPTL8 gene dysregulation, abrogating the normal function of the complex requiring both ANGPTL3 and ANGPTL8 would be considered relevant.
Applicant also states “correlation is not the same as causation”. However, a correlation is the first step in research to demonstrate an indirect or direct effect of a protein or a gene. Especially when this correlation is confirmed via association studies such as Meng (Meng, X. et al. “Association of circulating ANGPTL8 levels with renal dysfunction: a case-control study”. Frontiers in Public Health, Vol. 9 (September 2021), p: 710504).
Meng also admit that further studies would be required (page 6, “Conclusion” section). A strong correlation taken together with the known state of the art disclosed as disclosed by Gromada (WO2017/177181 A1, previously cited in Office Action dated 06/05/2024) using both ANGPTL3 and ANGPTL8 antibodies to treat hyperlipidemia, with a risk factor for hyperlipidemia and the consequence of kidney dysfunction (see Gromada et al., [0013], [0029], [0079]; claims 5 and 17). Gromada teaches selecting patient having oner or more risk factors such as moderate chronic kidney disease to be treated with anti-ANGPTL3 and anti-ANGPTL8 antibodies (see [0079]).
These correlations and studies, combined with Brown, Pisciotta, Aleksandrov, Wang and Li, demonstrate a need and motivation to design experiments and confirm the correlation and establish causation.
In this case, Brown teaches a method of treating diseases associated with ANGPTL3 expression and listed is also chronic kidney disease (see § [0193]). Wang teaches that genetic mimicry of ANGPTL3 inhibition is associated with improved kidney function (see Summary, page 1161) . Li teaches the direct impact of ANGPTL3 on glomerular epithelial cells as being a negative one (see Figure 2). Li also teaches that inhibition of ANGPTL3 pathway leads to improved permeability (see Figures 4 and 5).
Regarding Applicant’s arguments (pages 5-6) against Aleksandrov, “focusing on correlation as opposed to causation”, the same argument can be made that a first step in a research study is to establish correlation, than search for the acting signal pathway for an indirect or direct causation link. Aleksandrov teaches a relationship between circulating levels of ANGPTL3 itself, and kidney function in subjects presenting with different stages of diseases (see “Methods” section). This published study, even short, leads to motivation to combine the references.
Therefore, the method of treating a chronic kidney disease is rendered obvious by the combination of Brown, Pisciotta, Zou, Aleksandrov, Wang, and Li. The fact that ANGPTL3 having a unique dual role on lipid metabolism and kidney function, is rendered obvious by the combination of references.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.D./Examiner, Art Unit 1636 /NANCY J LEITH/Primary Examiner, Art Unit 1636
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